3 research outputs found
Inborn errors in the metabolism of glutathione
Glutathione (GSH) is a tripeptide present in all mammalian cells. It
takes part in several fundamental biological functions, including
handling of reactive oxygen species (ROS), detoxification of xenobiotics
and carcinogens, redox reactions, biosynthesis of DNA and leukotrienes,
as well as neurotransmission/neuromodulation. Oxidative stress may be
involved in the pathogenesis of several diseases, such as cancer,
ischemia/reperfusion injury, ageing, and neurodegenerative diseases. All
these conditions have also been associated with low levels of GSH. There
are very few patients with inborn errors in the metabolism of GSH, but
they give an opportunity to study the biological functions of GSH.
Glutathione is metabolized via the gamma-glutamyl cycle, which contains
six enzymes. In man, recessively inherited defects have been described in
4 of the 6 enzymes. A large inbred Dutch kindred were investigated
because of hemolytic anemia and low levels of GSH. A marked reduction in
the activity of gamma-glutamylcysteine synthetase was found in two family
members and a homozygous mutational defect was localized to the heavy
subunit of gamma-glutamylcysteine synthetase. However, the commonest - or
least unusual - defect in the gamma-glutamyl cycle is glutathione
synthetase (GS) deficiency. This condition has a very wide range of
disease manifestations. About 1/3 of the patients have died in the
neonatal period. The clinical characteristics of patients with GS
deficiency have been clarified, and a new classification based on the
severity of clinical signs proposed. Patients with mild disease have only
hemolytic anemia. Those with moderate GS deficiency are usually seen in
the neonatal period with metabolic acidosis, 5- oxoprolinuria and
hemolytic anemia. Patients with severe disease also develop progressive
neurological symptoms. It is tempting to speculate that the progressive
neurological symptoms are due to defective defense against oxidative
stress. A long-term follow-up study showed that an important prognostic
parameter to avoid damage to the CNS in patients with GS deficiency is
early supplementation with the antioxidant vitamins C and E. The fact
that 2/3 of the surviving patients with GS deficiency have no
neurological symptoms, may also be explained by the accumulation of
gamma-glutamylcysteine in mutant cells. This dipeptide contains both
reactive moieties of GSH - i.e., the gamma-glutamyl and sulthydryl
residues- which may therefore replace GSH. The genetic defects have been
studied in patients with deficiencies of GS and gamma-glutamylcysteine
synthetase. The mutations found in patients with GS deficiency have been
expressed in an E. coli system. Hitherto, no simple correlation has been
found between the GS mutation and the severity of the symptoms. As the
patients become older, new challenges must be considered -e.g., one woman
with moderate GS deficiency became pregnant. She had a normal delivery of
an apparently normal heterozygous neonate.
On the basis of our studies we conclude that low cellular levels of GSH
lead to damage of the CNS by reducing the ability to withstand oxidative
stress. The severity of the clinical symptoms depends on the degree of
GSH deficiency, but presumably also on other genetic and environmental
factors. Finally, we speculate that there are more patients with GS
deficiency than with y-glutamylcysteine synthetase deficiency because
they accumulate the dipeptide precursor gamma-glutamylcysteine that can
at least partly replace GSH